WO1998034942A2 - Dinucleotides et leur utilisation en tant que modulateurs d'epuration mucociliaire et de frequence des battements ciliaires - Google Patents

Dinucleotides et leur utilisation en tant que modulateurs d'epuration mucociliaire et de frequence des battements ciliaires Download PDF

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Publication number
WO1998034942A2
WO1998034942A2 PCT/US1998/002702 US9802702W WO9834942A2 WO 1998034942 A2 WO1998034942 A2 WO 1998034942A2 US 9802702 W US9802702 W US 9802702W WO 9834942 A2 WO9834942 A2 WO 9834942A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
amino
uridine
hydroxy
Prior art date
Application number
PCT/US1998/002702
Other languages
English (en)
Other versions
WO1998034942A3 (fr
Inventor
William Pendergast
Benjamin R. Yerxa
Janet L. Rideout
Suhaib M. Siddiqi
Original Assignee
Inspire Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/797,472 external-priority patent/US5900407A/en
Priority claimed from US08/798,508 external-priority patent/US5837861A/en
Priority to US09/101,395 priority Critical patent/US6348589B1/en
Priority to BR9807169-6A priority patent/BR9807169A/pt
Priority to DE69834392T priority patent/DE69834392T2/de
Priority to AU63242/98A priority patent/AU738907C/en
Priority to CA002279963A priority patent/CA2279963C/fr
Priority to JP53505598A priority patent/JP4531867B2/ja
Application filed by Inspire Pharmaceuticals, Inc. filed Critical Inspire Pharmaceuticals, Inc.
Priority to EP98907435A priority patent/EP0981534B1/fr
Priority to KR1019997007070A priority patent/KR100606131B1/ko
Priority to NZ337225A priority patent/NZ337225A/en
Publication of WO1998034942A2 publication Critical patent/WO1998034942A2/fr
Priority to NO19993776A priority patent/NO326718B1/no
Publication of WO1998034942A3 publication Critical patent/WO1998034942A3/fr
Priority to US10/007,451 priority patent/US6977246B2/en
Priority to US10/962,016 priority patent/US7223744B2/en
Priority to US11/690,385 priority patent/US7531525B2/en
Priority to US12/436,679 priority patent/US8008274B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Definitions

  • This invention relates to certain dinucleotides which increase the hydration of retained mucus secretions, stimulate the production of mucins and increase ciliary beat frequency to increase clearance of retained secretions.
  • Tear secretion can be stimulated from lacrimal accessory tissues via P2Y 2 and /or P2Y 4 purinergic receptor-mediated mechanisms similar to those which hydrate airway epithelia.
  • Dry eye disease is the general term for indications produced by abnormalities of the precorneal tear film characterized by a decrease in tear production or an increase in tear film evaporatioin, together with the ocular surface disease that results.
  • the pharmaceutical treatment of dry eye disease is mostly limited to administration of artificial tears (saline solution) to temporarily rehydrate the eyes.
  • relief is short lived and frequent dosing is necessary.
  • mucous secretions are removed via the mucociliary clearance
  • nucleoside phosphates such as uridine 5'-triphosphate (UTP) modulate all of the components of the MCC system.
  • UTP uridine 5'-triphosphate
  • UTP has been shown to increase cilia beat frequency in human airway epithelial cells in vitro (D. Drutz, et al., DrugDev. Res. 37(3), 185 (1996)).
  • R 4 is hydrogen, hydroxy, mercapto, amino, cyano, aralkoxy, C,. 6 alkylthio,
  • One or more compounds of general Formulas I, IA or IB may be administered separately or together, or separately or together with mucolytics such as DNAse or acetylcysteine.
  • Dosage levels of the order of from about 10 "7 M to about 10 "1 M, preferably in the range 10 "5 to 10 " 'M, are useful in the treatment of the above-indicated conditions.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • nucleoside mono-, di-, or triphosphate activated with a condensing agent such as, but not limited to, carbonyldumidazole or dicyclohexylcarbodiimide, with a second molecule of the same or a different mono-, di-, or triphosphate to form the desired dinucleotide polyphosphate; or a nucleoside phosphate, activated as above, may be condensed sequentially with a non-nucleoside mono-, di- or polyphosphate moiety, such as , but not limited to a monophosphate or pyrophosphate anion to yield the desired dinucleotide polyphosphate, the non-isolated intermediate in such a case being a mononucleotide polyphosphate; or a mono-, di- or polyphosphate moiety, activated as mentioned above, or in the form of an acid halide or other derivative reactive toward nucleophilic
  • Tetrasodium imidodiphosphate (Sigma, 0.05 mmol) was dissolved in water 0.5 mL) and applied to a column of Biorad AG-MP50 strong cation exchange resin (2 mL bed volume, 3 meq) in its tributylamine form. The column was eluted with water (- 10 mL), the eluate lyophilized dried by evaporation with dry DMF.
  • reaction mixture was evaporated to dryness under vacuum at room temperature, the residue dissolved in water (2 mL), and applied to a column of DEAE cellulose (2.5 x 50 cm bed volume) in the bicarbonate form.
  • the column was eluted with water ( ⁇ 250 mL), then with a gradient of
  • the 'H NMR spectrum of the aqueous solution indicated that the ethenylation had progressed about 50%, while the 31 P spectrum confirmed that the tetraphosphate chain remained intact.
  • Additional chloroacetaldehyde solution (0.25 mL) was added to the NMR solution and the mixture set aside for a further ten days. The solution was lyophilized, and the residue lyophilized again with deuterium oxide to remove exchangeable protons. The residue was partitioned between deuterium oxide and methylene chloride as before, and complete conversion to the ethenyl derivative confirmed by NMR spectroscopy.
  • the deuterium oxide solution was applied to a column of DEAE cellulose (2.5 x 30 cm bed volume) in the bicarbonate form.
  • the column was eluted with water (-250 mL), followed by a gradient of 0 to 0.5 M ammonium bicarbonate over 1000 mL. The progress of the elution was followed by monitoring absorbance of the eluate at 280 nm. The fraction eluting between 0.29 and 0.32 M was evaporated to dryness and desalted by repeated evaporations with deionized water to yield the title compound (1.584 ⁇ mol, 26.4% yield, quantitated by comparison of its absorbance at ⁇ max 273 nm with that of a standard solution of 3,N 4 - ethenocytidine 5 '-monophosphate).
  • 3'-Azido-3'-deoxythymidine 5 '-monophosphate (AZTMP) sodium salt 50 mg, 0.135 mmol was dissolved in water (1 mL) and applied to a column of Biorad AG-MP50 strong cation exchange resin in its tributylamine form. The column was eluted with water (- 10 mL) and the eluate lyophilized. The resulting tributylamine salt was condensed with uridine 5 '-cyclic trimetaphosphate (0.1 mmol) prepared by activation of UTP with dicyclohexylcarbodiimide (206 mg) essentially as described in Example 7.
  • d-GMP 2'-Deoxyguanosine 5 '-monophosphate
  • DMF 4mL
  • tributylamine 1.0 mL
  • UcTP uridine 5 '-cyclic metaphosphate
  • the solution was evaporated to an oil, dissolved in water (10 mL) and applied to a column of Sephadex DEAE (350 mL in a 4.5 x 22 cm column) in its bicarbonate form, pre-equilibrated with 0.25 M ammonium bicarbonate.
  • 2'-Deoxyinosine 5 '-monophosphate (d-IMP, Sigma, sodium salt 1.0 g) is converted to the free acid form with Dowex 50 (H + ) resin as described for UTP above.
  • the eluent is neutralized with tributylamine (2.0 mL) and the mixture concentrated to an oil under vacuum.
  • the resulting tributylamine salt is dried by evaporation with DMF, the residue dissolved in DMF (4.5 mL) and treated with uridine 5'-cyclic trimetaphosphate essentialy as described above to yield P'-(2'-deoxyinosine 5'-)P 4 -( uridine 5'-)tetraphosphate.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Otolaryngology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention concerne de nouveaux dinucléotides et de nouvelles formulations de ceux-ci, ces dinucléotides constituant des agonistes hypersélectifs du récepteur purinergique P2Y2 et/ou du récepteur purinergique P2Y4. Ces dinucléotides peuvent être utiles au traitement de maladies respiratoires obstructives chroniques, telles que la bronchite chronique, la dyskinésie ciliaire primaire (PCD), ou la mucoviscidose, et peuvent également prévenir la pneumonie due à l'impotence. En outre, de par leur capacité générale à éliminer les sécrétions muqueuses et à stimuler la fréquence des battements ciliaires, les composés de la présente invention sont également utiles au traitement de la sinusite, de l'otite moyenne, et de l'obstruction du canal lacrymo-nasal. Enfin, ils sont utiles au traitement de la kératoconjonctivite sèche et du décollement de la rétine.
PCT/US1998/002702 1997-02-06 1998-02-06 Dinucleotides et leur utilisation en tant que modulateurs d'epuration mucociliaire et de frequence des battements ciliaires WO1998034942A2 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
KR1019997007070A KR100606131B1 (ko) 1997-02-06 1998-02-06 디뉴클레오티드 및 그의 용도
NZ337225A NZ337225A (en) 1997-02-06 1998-02-06 Dinucleotides useful for treating chronic pulmonary obstructive disorder
BR9807169-6A BR9807169A (pt) 1997-02-06 1998-02-06 Dinucleotìdeos e uso dos mesmos como moduladores de depuração mucociliar e frequência de batimentos ciliares
DE69834392T DE69834392T2 (de) 1997-02-06 1998-02-06 Dinukleotide und ihre verwendungen
AU63242/98A AU738907C (en) 1997-02-06 1998-02-06 Dinucleotides and their use
CA002279963A CA2279963C (fr) 1997-02-06 1998-02-06 Dinucleotides et leur utilisation
JP53505598A JP4531867B2 (ja) 1997-02-06 1998-02-06 一定のジヌクレオチドおよび粘膜繊毛クリアランスおよび繊毛運動頻度のモジュレーターとしてのそれらの使用
US09/101,395 US6348589B1 (en) 1997-02-06 1998-02-06 Certain dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency
EP98907435A EP0981534B1 (fr) 1997-02-06 1998-02-06 Dinucleotides et leur utilisation
NO19993776A NO326718B1 (no) 1997-02-06 1999-08-04 Dinukleotider og farmasøytiske preparater omfattende slike, og anvendelser derav for fremstilling av medikamenter.
US10/007,451 US6977246B2 (en) 1997-02-06 2001-11-06 Certain dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency
US10/962,016 US7223744B2 (en) 1997-02-10 2004-10-07 Pharmaceutical formulation comprising dinucleoside polyphosphates and salts thereof
US11/690,385 US7531525B2 (en) 1997-02-10 2007-03-23 P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-)tetraphosphate, tetra-(alkali metal) salt, for treating cystic fibrosis
US12/436,679 US8008274B2 (en) 1997-02-10 2009-05-06 P1-(2′-deoxycytidine 5′-)P4-(uridine 5′-)tetraphosphate, tetra-(alkali metal) salt, for treating sinusitis

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/797,472 US5900407A (en) 1997-02-06 1997-02-06 Method of treating dry eye disease with uridine triphosphates and related compounds
US08/797,472 1997-02-06
US08/798,508 1997-02-10
US08/798,508 US5837861A (en) 1997-02-10 1997-02-10 Dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US08/797,472 Continuation-In-Part US5900407A (en) 1996-03-27 1997-02-06 Method of treating dry eye disease with uridine triphosphates and related compounds
US08/798,508 Continuation-In-Part US5837861A (en) 1996-03-27 1997-02-10 Dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency

Related Child Applications (4)

Application Number Title Priority Date Filing Date
US09/101,395 A-371-Of-International US6348589B1 (en) 1997-02-06 1998-02-06 Certain dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency
US09/774,752 Continuation-In-Part US6596725B2 (en) 1997-02-10 2001-01-30 Use of certain dinucleotides to stimulate removal of fluid in retinal detachment and retinal edema
US09/774,629 Continuation-In-Part US6952822B2 (en) 2000-06-30 2001-02-01 Program installation method, program installation system, program executing apparatus, and storage medium
US10/007,451 Continuation US6977246B2 (en) 1996-03-27 2001-11-06 Certain dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency

Publications (2)

Publication Number Publication Date
WO1998034942A2 true WO1998034942A2 (fr) 1998-08-13
WO1998034942A3 WO1998034942A3 (fr) 2000-01-06

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Application Number Title Priority Date Filing Date
PCT/US1998/002702 WO1998034942A2 (fr) 1997-02-06 1998-02-06 Dinucleotides et leur utilisation en tant que modulateurs d'epuration mucociliaire et de frequence des battements ciliaires

Country Status (16)

Country Link
US (2) US6348589B1 (fr)
EP (1) EP0981534B1 (fr)
JP (1) JP4531867B2 (fr)
KR (1) KR100606131B1 (fr)
CN (1) CN1262556C (fr)
AT (1) ATE325129T1 (fr)
AU (1) AU738907C (fr)
BR (1) BR9807169A (fr)
CA (1) CA2279963C (fr)
DE (1) DE69834392T2 (fr)
DK (1) DK0981534T3 (fr)
ES (1) ES2264197T3 (fr)
NO (1) NO326718B1 (fr)
NZ (1) NZ337225A (fr)
PT (1) PT981534E (fr)
WO (1) WO1998034942A2 (fr)

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999005155A2 (fr) * 1997-07-25 1999-02-04 Inspire Pharmaceuticals, Inc. Procede de production de masse de di(uridine 5'-tetraphosphate) et de ses sels
WO1999061012A2 (fr) * 1998-05-22 1999-12-02 Inspire Pharmaceuticals, Inc. Dinucleotides therapeutiques et leurs derives
WO2000039145A1 (fr) * 1998-12-23 2000-07-06 The University Of North Carolina At Chapel Hill Transfert genique cible utilisant des recepteurs couples a une proteine g
WO2001002416A1 (fr) * 1999-06-30 2001-01-11 Yamasa Corporation Cristaux dinucleotidiques
WO2001012644A1 (fr) * 1999-08-17 2001-02-22 Adani, Alexander Dinucleoside 5',5'-tetraphosphates comme inhibiteurs de transcriptase inverse virale et de virus
WO2001045691A2 (fr) * 1999-12-22 2001-06-28 Inspire Pharmaceuticals, Inc. Methode de traitement de maladies du tractus gastro-intestinal au moyen d'agonistes de recepteurs purinergiques
US6319908B1 (en) 1996-07-03 2001-11-20 Inspire Pharmaceuticals, Inc. Method for large-scale production of di(uridine 5′-tetraphosphate) and salts thereof
WO2001087913A2 (fr) * 2000-05-12 2001-11-22 Inspire Pharmaceuticals, Inc. Procede de traitement de la degenerescence retinienne avec des agonistes de recepteur purinergique
WO2001091795A1 (fr) 2000-05-30 2001-12-06 Santen Pharmaceutical Co., Ltd. Promoteurs de l'extension de l'epithelium corneen
US6331529B1 (en) 1999-02-26 2001-12-18 Inspire Pharmaceuticals, Inc. Method of promoting mucosal hydration with certain uridine, adenine and cytidine diphosphates and analogs thereof
WO2002048165A2 (fr) * 2000-12-15 2002-06-20 Pharmasset Ltd. Agents antiviraux utilises dans le traitement des infections par les flaviviridae
WO2002060454A2 (fr) * 2001-01-30 2002-08-08 Inspire Pharmaceuticals, Inc. Utilisation de dinucleoside polyphosphate pour stimuler l'elimination de fluide dans les troubles retiniens
WO2002062816A1 (fr) * 2001-02-07 2002-08-15 Celltech R & D Limited Nucleotides et dinucleotides non naturels
US6462028B2 (en) 1997-07-25 2002-10-08 Inspire Pharmaceuticals, Inc. Method of promoting cervical and vaginal secretions
WO2003011885A1 (fr) * 2001-07-25 2003-02-13 Celltech R & D Limited Nucleotides et dinucleotides a liaison carbone non naturels
US6548658B2 (en) * 1997-07-25 2003-04-15 Inspire Pharmaceuticals, Inc. Di-(uridine 5′)-tetraphosphate and salts thereof
WO2003030892A1 (fr) * 2001-10-11 2003-04-17 Alcon, Inc. Methodes de traitement de l'oeil sec
US6596725B2 (en) 1997-02-10 2003-07-22 Inspire Pharmaceuticals, Inc. Use of certain dinucleotides to stimulate removal of fluid in retinal detachment and retinal edema
GB2385788A (en) * 2002-01-18 2003-09-03 Inspire Pharmaceuticals Inc Purinergic receptor ligands for use in reducing intraocular pressure
US6673779B2 (en) 1996-03-27 2004-01-06 Inspire Pharmaceuticals, Inc. Method of treating ciliary dyskinesia with dinucleoside polyphosphate compounds or UTP analogues
US6703376B2 (en) 1996-07-23 2004-03-09 Inspire Pharmaceuticals, Inc. Use of uridine triphosphates and related compounds for the prevention and treatment of pneumonia in immobilized patients
US6713458B1 (en) 1997-07-25 2004-03-30 Inspire Pharmaceuticals, Inc. Therapeutic uses of di(uridine 5′)-tetraphosphate and salts thereof
EP1450820A2 (fr) * 2001-11-06 2004-09-01 Inspire Pharmaceuticals, Inc. Methode de traitement et de prevention de maladies inflammatoires
US6818629B2 (en) 1997-02-10 2004-11-16 Inspire Pharmaceuticals, Inc. Pharmaceutical formulation comprising P1-(2'-deoxycytidine 5'-)P4-(uridine 5'-) tetraphosphate
US6867199B2 (en) 2000-08-21 2005-03-15 Inspire Pharmaceuticals, Inc. Dinucleoside polyphosphate compositions and their therapeutic use
US6872710B2 (en) 1997-07-25 2005-03-29 Inspire Pharmaceuticals, Inc. Di(uridine 5′)-tetraphosphate and salts thereof
JP2005526046A (ja) * 2002-02-27 2005-09-02 インスパイアー ファーマシューティカルズ，インコーポレイティド 上皮及び網膜組織疾患の治療のための組成物及び治療方法
US6977246B2 (en) 1997-02-06 2005-12-20 Inspire Pharmaceuticals, Inc. Certain dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency
WO2006016115A2 (fr) * 2004-08-11 2006-02-16 University College Cardiff Consultants Limited Procédé et moyens de délivrance améliorée de médicaments pulmonaires
US7018985B1 (en) 2000-08-21 2006-03-28 Inspire Pharmaceuticals, Inc. Composition and method for inhibiting platelet aggregation
US7078391B2 (en) 1997-02-10 2006-07-18 Inspire Pharmaceuticals, Inc. Method of treating edematous retinal disorders
WO2006082397A1 (fr) * 2005-02-03 2006-08-10 Imuthes Limited Nouvelles utilisations de derives de polyphosphate de dinucleotides
US7109181B2 (en) 2001-06-25 2006-09-19 Inspire Pharmaceuticals, Inc. Joint lubrication with P2Y purinergic receptor agonists
US7223744B2 (en) 1997-02-10 2007-05-29 Inspire Pharmaceuticals, Inc. Pharmaceutical formulation comprising dinucleoside polyphosphates and salts thereof
EP1895840A2 (fr) * 2005-06-29 2008-03-12 Inspire Pharmaceuticals, Inc. Agonistes du recepteur de p2y6 destines au traitement de maladies pulmonaires
US7618949B2 (en) 2000-08-21 2009-11-17 Inspire Pharmaceuticals, Inc. Drug-eluting stents coated with P2Y12 receptor antagonist compound
JP2009544754A (ja) * 2006-07-28 2009-12-17 アプライド バイオシステムズ， エルエルシー ジヌクレオチドｍｒｎａキャップアナログ
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ES2264197T3 (es) 2006-12-16
CA2279963A1 (fr) 1998-08-13
AU738907B2 (en) 2001-09-27
PT981534E (pt) 2006-09-29
US20020082417A1 (en) 2002-06-27
US6977246B2 (en) 2005-12-20
JP4531867B2 (ja) 2010-08-25
CA2279963C (fr) 2008-04-22
CN1292795A (zh) 2001-04-25
US6348589B1 (en) 2002-02-19
KR20000070807A (ko) 2000-11-25
EP0981534A2 (fr) 2000-03-01
ATE325129T1 (de) 2006-06-15
NO326718B1 (no) 2009-02-02
NO993776L (no) 1999-10-06
NO993776D0 (no) 1999-08-04
WO1998034942A3 (fr) 2000-01-06
AU6324298A (en) 1998-08-26
EP0981534B1 (fr) 2006-05-03
DE69834392T2 (de) 2007-02-08
KR100606131B1 (ko) 2006-07-31
CN1262556C (zh) 2006-07-05
DK0981534T3 (da) 2006-09-04
JP2001526635A (ja) 2001-12-18
NZ337225A (en) 2002-03-28
AU738907C (en) 2002-05-16
BR9807169A (pt) 2000-06-06
DE69834392D1 (de) 2006-06-08

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